This is a research-intensive proposal designed to provide the applicant with the scientific and professional development skills necessary to achieve her future career goal of becoming an independent investigator in the field of metabolism and diabetes research. The research and training goals of this application are detailed below: Obesity dramatically increases the risk of a number of metabolic disorders, including insulin resistance and type 2 diabetes. Recent studies demonstrate that immune cells, including M1 polarized macrophages, accumulate in the adipose (fat) tissue during obesity and contribute to the development of systemic metabolic dysfunction. However, the signaling pathways that promote macrophage inflammation and accumulation in adipose tissue are incompletely understood and represent potential targets for therapeutic intervention. The research goal of this application is to define the role of deoxyhypusine synthase (DHS) in the generation of adipose tissue macrophage inflammation and systemic metabolic dysfunction during obesity. DHS is the key enzyme responsible for activation of the translation factor, eIF5A. This activation occurs through the addition of a hypusine modification to eIF5A. In my preliminary data, I have shown that DHS-mediated hypusination of eIF5A promotes the translation of inflammatory mRNAs (including inducible nitric oxide synthase and TNF-a converting enzyme) during M1 macrophage polarization. Furthermore, these same pathways are activated in macrophages residing in the adipose tissue of obese mice. In this application, the role of DHS in promoting adipose tissue macrophage inflammation and systemic metabolic defects during obesity will be tested in two specific aims. In Aim 1, I will (1) define mechanisms by which DHS regulates the translation of Nos2 and Adam17/TACE, and (2) utilize a targeted approach to identify and validate additional inflammatory mRNAs that are transnationally controlled by DHS. To further define the metabolic role of DHS, a transgenic mouse model with a macrophage-specific deletion of DHS has been created. In Aim 2, the immunologic and metabolic phenotype of these mice will be comprehensively defined. Together, the research aspects of this proposal will determine the role that DHS plays in promoting obesity-associated metabolic dysfunction. The training goal of this proposal is to provide the applicant with the scientific and professional skills needed to succeed as an independent investigator in academia. Through the completion of these studies, I will gain an expertise in the study of the regulation of mRNA translation and the breeding and maintenance of transgenic mouse lines. In addition, participation in career development workshops, departmental seminars, lab meetings, journal clubs, and scientific meetings will provide a comprehensive career development experience that will ensure the success of the applicant.